PI3K/Akt and ERK/MAPK Signaling Promote Different Aspects of Neuron Survival and Axonal Regrowth Following Rat Facial Nerve Axotomy

Abstract

The ERK/MAPK and PI3K/Akt signaling pathways play important role in neuronal survival and axonal regeneration after peripheral nerve injury. However, the relative importance and degree of functional overlap of the two pathways are still debated due to lack of in-vivo data. We used rats which underwent a facial nerve axotomy, and examined subsequent ERK/MAPK and PI3K/Akt signaling activity by quantifying phosphorylation of ERK and Akt. We also assessed the survival rate of facial neurons, number of regenerated axons, and the length of axonal regrowth in axotomized animals treated with an inhibitor of ERK/MAPK (U0126) or PI3K/Akt (LY294002) phosphorylation, or with vehicle. Axotomy increased phosphorylation of ERK and Akt in the facial nucleus 7 days after injury. The inhibition of ERK phosphorylation significantly reduced the length of regenerated axons, but not the other parameters. Inhibition of Akt phosphorylation significantly reduced the survival rate of facial neurons and the number of new axons, as well as the length of regenerated axons. The results indicate that facial nerve injury activates the ERK/MAPK and PI3K/Akt signaling pathways in the facial nerve nucleus and its axons. However, the pathways promoted aspects of regeneration with only slight overlap: PI3K/Akt signaling improved the survival of neurons, as well as axonal growth and branching, whereas ERK/MAPK signaling promoted only axonal extension.